Dry eye disease (DED), an immune disorder of largely unknown pathogenesis, is characterized by sustained ocular surface and in particular corneal inflammation, and disruption of the ocular surface epithelial barrier, which in severe cases can lead to blindness from corneal ulceration and scarring. DED has a very high prevalence, almost triple that of age-related macular degeneration, affecting many millions of individuals in the US alone, and its prevalence is set to double in the coming decades with the aging of the population. Current expenditures for treating DED surpass $1 billion dollars annually, and because it often affects visual function in working adults, it leads to lost productivity by impacting job performance. While immunity and inflammation have been implicated in its pathogenesis, very little is known about the precise immunopathogenic mechanisms of DED except that disease activity is sustained by ongoing activation and infiltration of the ocular surface by CD11b+ monocytes and CD4+ T cells. We have recently demonstrated that pathogenic T cells in DED are generated in the draining lymph nodes, but the cellular and molecular mechanisms that (i) mediate trafficking of immune cells from the eye to the lymphoid tissues to prime T cells, (ii) promote T cell stimulation and (iii) T cell homing onto the ocular surface remain unknown. In addition, (iv) while corneal nerve loss and dysfunction are important aspects of DED, very little is understood about the mechanisms that effect nerve degeneration in DED. The objectives of this project are to (i) precisely define the molecular and cellular pathogenic mechanisms of DED, and (ii) identify possible targets for treatment of DED. We hypothesize that pathogenesis of DED is associated with mobilization of mature corneal antigen-presenting cells (APC) to the lymphoid compartment where they can prime T cells, which can in turn home to the ocular surface to induce epithelial disease and neuropathy. We propose four specific aims to test this hypothesis in a validated and well-characterized mouse model of DED. The Specific Aims focus on identifying the mechanisms that (1) induce maturation of corneal APC, (2) facilitate APC trafficking to the lymphoid compartment, (3) lead to generation and peripheralization of different (Th1 and Th17) pathogenic CD4+ T cell subsets, and (4) cause corneal nerve degeneration. It is anticipated that the overall impact of this research will be significant given the high prevalence of DED and the general dearth of knowledge regarding its immunopathogenesis. PUBLIC HEALTH RELEVANCE: Dry eye disease is an inflammatory disorder of the ocular surface, associated with visual dysfunction and heightened risk of corneal scarring and infection, with as of yet poorly understood immunopathogenesis. We propose here to determine the specific immune-based cellular and molecular pathogenic elements of dry eye disease. The hope is that precise understanding of distinct pathogenic mechanisms will yield important therapeutic targets which could be useful in the management of the millions of Americans suffering from severe dry eye, and tens of millions of others with less severe symptoms.